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Laura Alejandra Ramírez-Tirado



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    EP1.12 - Small Cell Lung Cancer/NET (ID 202)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.12-16 - CD47 Expression and Prognosis in Patients with Small Cell Lung CancerCD47 Expression and Prognosis in Patients with Small Cell Lung Cancer (ID 2935)

      08:00 - 18:00  |  Author(s): Laura Alejandra Ramírez-Tirado

      • Abstract

      Background

      CD47 is an integral membrane protein expressed in all cells. CD47 present two opposing roles in cell survival. CD47 can interact with signal-regulatory protein-α (SIRP-a) on macrophages, prevents phagocytic clearance. Besides, CD47 signaling through the thrombospondin-1 limits self-renewal and suppresses expression of the stem cell transcription factors cMyc, Sox2, Oct4, and Klf4 in non-transformed cells. Data on the clinical significance of CD47 expression in patients with small cell lung cancer remain limited.

      Method

      Forty-five naive patients with small cell lung cancer diagnosis were evaluated. Tumor samples obtained by biopsy or surgical resection, were collected for CD47 evaluation. Tumor samples were scored according to the fraction of stained cells at each intensity. The staining intensity of the cell membrane was scored within a scale ranging from 0-3. To determine the prognostic and predictive biomarkers of CD47, patients were stratified according to a cutoff point. This cutoff was optimized as a function of overall survival (OS) using the X-tile and Cutoff Finder software

      Result

      Preliminary results showed that CD47 was present in 26.7% of population. We stratified the CD47 in two cohorts: CD47 positive-negative and a score of CD47>80. The CD47>80 was present mainly in patient with more than 60 years old (35% vs. 8.0%, p=0.024). Longer overall survival was associated with ECOG-PS 0-1 (20.2 vs. 6.9 p=0.001), disease stage IIIB (49.4 vs. 8.0, p=0.020), absent of CNS metastases (14.1-6.8, p=0.016) and absent of pleural effusion (16.2 vs. 6.99, p=0.002). Interestingly, patient with CD47 positive present better OS (10.8 vs. 6.99, p=0.485) but not reaching significance and patient with a score of CD47>80 have better OS (14.0 vs 9.2, p=0.296).

      Conclusion

      Immune checkpoint CD47 expressed on the surface of tumor cells allows them to escape immunosurveillance. We previously reported that high CD47 expression was associated with the presence of somatic EGFR mutations in patients with NSCLC. In these patients, high CD47 expression was an independent prognostic factor of worse progression-free survival. Recent studies have indicated that the signal-regulatory protein (SIRP)α–CD47 pathway regulate a phagocytosis checkpoint in macrophages and other innate immune cells. In contrast, in this report we found that high CD47 expression was associated with <60 years old patient and better overall survival. Previously, studies in small cells lug cancer express high levels of CD47 and the blocking of CD47 enhances phagocytosis inhibits tumor growth. CD47 have a dual role, when interact with SIRPα avoid clearance of cells, but it interacts with thrombospondin 1 inhibits cell cycle progression and induces senescence in endothelial cells. Previous studies have shown that the protein TSP1 is as potent inhibitor of angiogenesis and its antiangiogenic activity is mediated by its receptors, CD36 and CD47. In conclusion CD47 have different function according to the ligand, and is a potential biomarker in cancer

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    MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA07.08 - The Role of a Cachexia Grading System in Patients with NSCLC Treated with Immunotherapy: Implications for Response and Survival (Now Available) (ID 2046)

      13:30 - 15:00  |  Author(s): Laura Alejandra Ramírez-Tirado

      • Abstract
      • Presentation
      • Slides

      Background

      The association between cancer-induced weight-loss (CIWL) and poor clinical outcomes is well established. However, many of these studies were performed in the chemotherapy era. Meanwhile, current standard of care for NSCLC patients has shifted towards the more efficacious immunotherapy agents (IO). IO has improved survival outcomes, nonetheless clinicians face the challenge of identifying who will derive substantial clinical benefit from these more costly agents. Response to IO is influenced by several patient-related factors, including microbiome, medications, and nutritional status.

      Method

      In this study we sought to evaluate the effect of cachexia in survival of NSCLC patients undergoing treatment with IO. Included patients had advanced NSCLC (IIIB, IV), who received IO agents in any line of therapy, and had a good performance status. All the patients were evaluated by the nutritionist specialist and were graded according to a previously documented cachexia scale which takes into consideration body mass index (BMI) and weight loss in order to stratify patients into 5 risk categories (0 [pre-cachexia] - 4 [refractory cachexia]). Primary endpoint was overall survival (OS), secondary endpoints included objective response rate (ORR) and progression-free survival.

      Result

      A total of 181 patients met the inclusion criteria and were included in the analysis. Among these 82 (45%) were classified in the first category (risk grade 0-1 [low risk]), 83 (46%) were classified in the second category (risk grade 2-3[intermediate risk]) and 9% were in the third category (risk grade 4 [high risk]). Patients classified as low-risk had a significantly longer OS compared to those with intermediate or high risk (22.4 months [95%CI: 18.7-26.1] vs. 15.7 [95%CI: 10.8-20.7] vs. 3.9 [0.0-7.8]; p<0.001; Hazard ratio: 1.81 [1.29-2.53]; p<0.001). In the multivariate analysis ORR, hemoglobin and risk category were independent factors associated with OS. Grade of cachexia was also significantly associated with ORR, with low-risk patients having a significantly higher ORR compared to intermediate and high-risk patients (36.6% vs. 17.3% vs. 25%; p=0.021). PFS was also influenced by risk category, with low risk patients having a longer PFS compared with intermediate and high-risk patients. diapositiva1.jpg

      Conclusion

      Cachexia is independently associated with worse OS in NSCLC patients who receive IO, while better nutritional status is related to higher ORR, highlighting a potential role for nutritional assessment in the selection of patients who are candidates for IO. Early assessment of nutritional status in these patients is imperative in order to timely diagnose and treat anorexia-cachexia and improve outcomes.

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    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA11.03 - Pembrolizumab Plus Docetaxel Increases Progression-Free Survival Compared with Docetaxel Alone in Previously Treated Advanced Non-Small Cell Lung Cancer Patients (Now Available) (ID 2017)

      14:00 - 15:30  |  Author(s): Laura Alejandra Ramírez-Tirado

      • Abstract
      • Presentation
      • Slides

      Background

      Immunotherapy is now the standard of care for non-small cell lung cancer patients without actionable mutations, due to a clear survival benefit in large phase III trials, further this benefit can be translated into the first-line setting, alone or in combination with chemotherapy. Nonetheless, due to several circumstances many patients do not receive immunotherapy as first-line. The effect of the combination therapy with pembrolizumab plus docetaxel in previously-treated NSCLC patients has not been prospectively assessed.

      Method

      In this phase II clinical trial, we evaluated the effect of a combination therapy with pembrolizumab plus Docetaxel (PD) compared with Docetaxel (D) for the treatment of advanced NSCLC patients who had progressed to previous lines of therapy. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety profile.

      Result

      Eighty patients met the inclusion criteria and were enrolled in the study, among which 78 were randomized 1:1. Forty patients were allocated to receive PD, while thirty-eight were allocated to receive D. Baseline characteristics, including sex, age, tobacco index, performance status and EGFR mutation were well-balanced between both arms of the trial. We found a statistically significant difference in terms of ORR (42.5% vs. 15.8%; OR: 3.9 [95%CI: 1.34-11.5]; p=0.01), in patients receiving PD compared with D alone. Further, patients receiving PD had a significantly longer PFS compared with those receiving D monotherapy (9.5 months [95%CI: 4.2-NR] vs. 3.9 [95%CI: 3.2-5.7]; HR: 0.24 [95%CI: 0.13-0.46]; p<0.001). In the multivariate analysis the therapeutic intervention was an independently associated factor with better PFS (Figure). In terms of safety, a total of 22.5% vs. 5.3% of patients experienced any-grade pneumonitis in the PD and D arm of the trial respectively (p=0.048), while 27.5% vs. 16% experienced any-grade hypothyroidism (p=0.20). No new safety signals were identified.

      Conclusion

      Patients who receive the combination therapy have a significantly increased ORR and PFS, with a significant decrease in the hazard of progressing. This work was performed through a grant from MSD (Investigator Initiated Study). The sponsor did not have any role in the acquisition or interpretation of the data.


      pfs_figure 1.png
      Figure. Kaplan-Meier curve for the progression-free survival of patients in the experimental (P+D) vs. the control (D) arm of the trial.

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    P2.08 - Oligometastatic NSCLC (ID 172)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Oligometastatic NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.08-04 - Stereotactic Ablative Radiation Therapy to Lung Metastases Associates with Better Outcomes in Oligometastatic Lung Cancer: Prospective Study (Now Available) (ID 2919)

      10:15 - 18:15  |  Author(s): Laura Alejandra Ramírez-Tirado

      • Abstract
      • Slides

      Background

      Nearly 7% of stage IV Non-Small cell Lung Cancer (NSCLC) patients present oligometastatic disease at diagnosis. These patients can benefit from definitive treatment to primary tumour and loco-ablation of metastases. The use of stereotactic ablative radiotherapy (SABR) has demonstrated high rates of local control and survival improvement in early disease stage. The aim of this study is to evaluate Progression Free Survival (PFS), Overall survival (OS) and toxicity of patients with oligometastatic NSCLC treated with Stereotactic ablative radiotherapy (SABR) to lung metastases.

      Method

      A prospective study was conducted with oligometastatic NSCLC patients. From August 2014 to April 2019, with a median follow up of 13 months, forty-seven patients were enrolled. All patients received systemic therapy according to international guidelines. Then, patients without progression to systemic treatment, received SABR to lung metastases (30-60 Gy in 2-8 fractions) to the thoracic lesion (primary or metastatic) depending on location, size and number of lesions, always keeping BED (Biologically Effective Dose) >100 Gy at isocenter. This study was approved by Ethic and Research comitees at Instituto Nacional de Cancerología (CEI/799)(013/014/ICI).

      Result

      Most patients were women (59.6%), with a mean age of 58.9 years. Although two-thirds of patients were ever smokers (66.0%), most of them were light smokers. The most common histology was adenocarcinoma (87.2%). Contralateral lung was the most common metastatic site (40.4%). Half of the patient harbour at least one mutation, EGFR Exon 19 deletion was the most frequent mutation (38.3%). Patients received chemotherapy and EGFR-TKIs as 1st-line treatment in the 61.1% and 38.9%, respectively. All patients received SABR, response to treatment was as follows: disease control rate was 91.5%, partial response 14.9% and complete response 63.8%. Among those with disease progression, median time to systemic progression after SABR treatment was 5.4 months (95% 2.4-8.9 months). PFS since beginning of any treatment was not reached, since only 18 patients (38.3%) had disease progression. Until now only 4 patients (8.5%) had died, thus OS is not reached. Radiographic pneumonitis was observed in 72.2% (13 patients). Grade 1, 2 and 3 pneumonitis were observed in the 69.2% (9/13), 7.7% (1/13) and 23.1 (3/13) of the patients with pneumonitis.sabr figure.jpg

      Conclusion

      SABR is a suitable and has a moderate toxicity profile. SABR is a therapeutic option for patients with oligometastatic NSCLC. SABR have shown to improve local control and increase progression-free survival. Future clinical trials are required to evaluate SABR against other treatment modalities.

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